Studies have shown CXCL12 (also called stromal cell-derived factor-1 or SDF-1) and CXCR4, a chemokine and chemokine receptor pair play important roles in hematopoiesis, multiple stages of tumorigenesis, and embryonic development (Broxmeyer, H. E. et al., Int. J. Hematol. 2001, 74, 9-17; Horuk, R., Nat. Rev. Drug Discov. 2009, 8, 23-33). For example, activation of CXCR4 by CXCL12 has shown to direct leukocyte chemotaxis in the immune system in response to inflammation and progenitor cell migration during embryologic development. Activation of CXCR4 by CXCL12 has also been shown to mediate signaling pathway that is involved in breast cancer metastasis and memory T cell migration (Orimo, A., et al., Cell 2005, 121, 335-348).
CXCR4, a G-protein-coupled receptor also known as fusin or CD184 (cluster of differentiation 184), is constitutively- or over-expressed in a wide variety of human cancers, promoting local tumor cell proliferation, survival and angiogenesis (Huang, E. H., et al., J. Surg. Res. 2009, 155, 231-236). It has also been reported that CXCR4 is a co-receptor for HIV entry and infection of host cells and has been evaluated as a potential HIV therapy (Tamamura, H., et al., Biochem. Biophys. Res. Commun. 1998, 253, 877-882; Oberlin, E. et al., Nature, 1996, 382, 833-835).
Stromal cell-derived factor-1 (SDF-1/CXCL12) is constitutively expressed at high levels by bone marrow stromal cells (Nagasawa T., et al., Proc. Natl. Acad. Sci. USA 1994, 91, 2305-2309), and it is a highly efficient chemotactic factor for T cells, monocytes, pre-B cells, dendritic cells and hematopoietic progenitor cells (Baggiolini M., Nature 1998, 392, 565-568; Moser B., et al., Nat. Immunol. 2001, 2, 123-128). Targeted disruption in mice of either the SDF-1 or CXCR4 gene results in a very similar phenotype, is lethal and accompanied by many severe developmental defects, including the absence of both lymphoid and myeloid hematopoiesis in the fetal bone marrow (Zou, Y. R. et al., Nature 1998, 393, 595-599). In addition, it has been shown that SDF-1 and CXCR4 play a critical role in the engraftment of hematopoietic stem cells to the bone marrow (Peled A., et al., Science 1999, 283, 845-848).
In view of the involvement of CXCR4/SDF-1 signaling pathway in these serious diseases, this signaling pathway is considered an important therapeutic target.
AMD3100, a bicyclam CXCR4 antagonist, has been approved by FDA in combination with granulocyte-colony stimulating factor (G-CSF) for use in hematopoietic stem cell mobilization for transplantation of stem cells in patients with multiple myeloma and non-Hodgkins lymphoma. AMD070, another small molecule CXCR4 antagonist, has progressed to Phase II clinical trials for HIV infection. CTCE9908, a bivalent (dimeric) peptide CXCR4 antagonist, has been explored as a treatment for cancer. Based on an initial lead T140, a disulfide cyclic peptide, Fujii and co-workers further developed FC131, a cyclic pentapeptide lactam CXCR4 antagonist, which inhibits 125I-SDF-1 binding to CXCR4 transfectants with an IC50 of 3 nM (Fujii et al., Angew. Chem. Int. Ed. 2003, 42:3251-3253; Tamamura, et al. Bioorg. Med. Chem. Lett. 2000, 10, 2633-2637). More recently, a cyclic peptide lactam as an antagonist for CXCR4 was evaluated in Phase II clinical trial for the treatment of kidney cancer (Peng, S., et al., Mol. Cancer Ther. 2015, 14, 480-490).
Despite these research efforts, there exists a need for improved CXCR4 antagonists that are potent and selective as a therapeutic treatment option.